Tobacco-smoking is the single major cause of cancer mortality in the US, and is a risk factor for a number of cancers including lung, upper aero-digestive tract, bladder and pancreas. Current strategies aimed at the control of lung cancer remain largely unsuccessful. Early detection remains the key to increased survival. Identification of individuals who are at increased risk to tobacco-induced cancers would aid public health by focusing the screening to a limited set of smokers who are most susceptible to tobacco-induced lung cancer. Inefficient DNA repair is a characteristic that increases the risk for an individual to get tobacco-induced lung cancer. The current paradigm is to evaluate DNA repair capacities using specific carcinogens with a generalized DNA repair test. The problem is that tobacco contains multiple carcinogens that produce a variety of DNA damage with a range of mutagenicities that are repaired by multiple mechanisms. The long-term goal of this project is to develop highly specific DNA repair tests that can measure the repair capacity of multiple DNA adducts simultaneously. The current goal is to develop and validate an HPLC-MS/MS assay that can measure the repair capacity of individual to ten DNA adducts that form from two of the most potent tobacco smoke carcinogens, benzo[a]pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. The hypothesis that we will test is that the risk of adeno- or squamous cell carcinoma is dependent of the repair of specific DNA adducts but not others. This hypothesis will be tested in two aims. First, a highly specific HPLC-MS/MS assay that can measure ten DNA adducts will be developed and validated. Second, the hypothesis will be tested in a hospital-based case-control study. This project can change the paradigm by which DNA repair assays are conducted in which the adduct chosen to be analyzed for repair will be based upon an understanding of the etiology of the cancer.